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	Simil